唐氏综合症（Down syndrome，DS）是最常见的先天性智力发育迟缓性疾病。该症发病率高，患者常出现早发性老年性痴呆。近年，因初产龄升高和环境因素等原因，我国DS的发病率出现升高趋势。然而，对于已出生的患儿，目前仅能以特殊教育改善其学习能力，尚无任何有效药物治疗手段。长期以来，因动物模型难以真实反映人类21号染色体三倍化造成的病理改变，研发新的人源性DS模型并基于此开展DS研究是领域内迫切需要解决的重要问题。植物多酚具有调控DS及相关疾病的作用。本项目中，申请人基于前期基础，将创新性地运用组合天然产物化学研究策略，建立何首乌属植物多酚的结构多样性样品库；采用学院建立的新型人源化DS脑发育模型，以天然小分子化合物为探针，围绕人DS脑星形胶质细胞（DS-Astro）发育异常这一重大问题，筛选可挽救DS-Astro毒性表型的小分子化合物，探究DS的发病机理，以期发现新型抗DS活性天然药物。

Down Syndrome (DS) is the most common chromosomal abnormality. In fact, about 95% of affected individuals have the free trisomy of human chromosome 21 i.e. an extra copy of chromosome 21, and their chromosome count is 47. The leading cause of trisomyis attributed to meiotic nondisjunction which occurs mainly in the ovum although the reason for this phenomenon is not completely clear. Clinically, DS is a neurodevelopmental disease and the most frequent genetic cause of intellectual disability characterized by symptoms of premature aging as well as cognitive decline. The typical features of DS are atypical craniofacial profile composed of a combination of flat facial projections, epicanthic folds, and protruding tongue. Affected persons have from mild to severe mental retardation and IQ varies between 25 and 50. Although the overall prognosis of DS has increased over the last decade owing to scientific advances in treatment against infections, DS remains uncured. The majority of patients that reach middle ages develop histopathological and neurochemical features which mimic Alzheimer’s disease (AD) and related dementias. Thus, the investigation on the corresponding molecular basis of DS will increase our understanding of the neurobiology of AD and identifying efficacious drug targets...Polyphenols are secondary metabolites of plants largely found in many fruits, vegetables, cereals and even beverages, and thus represent important components of the human diet. Increasing studies have showed the potential beneficial effects of plant polyphenols on human health. Extensive studies have been carried out to discuss the protective effects of polyphenols against diseases like cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. Limited investigations have performed to evaluate the potential therapeutic effects of these natural products on neurodevelopmental disorders associated with intellectual disability, such as Down syndrome (DS), for which mitochondrial dysfunctions and oxidative stress are hallmarks and contribute to the deleterious symptoms and cognitive decline. Most recently, a preliminary study conducted by our research group on the effect and potential molecular mechanism of action of some phenolic compounds isolated from the herbs Fallopia multiflora (Thunb.) Harald (well-known as “he-shou-wu” in China) in reversing phenotypical alteration in DS. This project will enable us to establish a standardized specimen bank for natural polyphenols from plant species of Fallopia genus, investigate on their structures, natural sources, and the evaluation of their biological activities for the management of Down syndrome and related disorders, as well as discuss the structures and activities relationship (SAR) of relevant plant-derived polyphenols from the Fallopia plants. In summary, under the financial support of the present research program, a specimen bank natural products, especially plant polyphenols, will be established from plants species of the genus Fallopia and assisted by chemical modification; the effects of different constituents on the expressions of S100B/IFNAR1/ IFNAR2 and Jak-STAT signling pathway will be investigated in DS chimeric mice model; the SAR analysis will be conducted; and the structural modification of the bioactive molecules will be prepared and biological activities against DS and their mode of actions will also be further studied, with an aim to discover more useful natural products that function as small molecular probes for the DS and related disorders.